1995 by Vera
Mastey. All rights reserved. 1995 by Vera
Mastey. All rights reserved.
This report is distributed through the Drugs and Devices Information Line at the Harvard School of Public Health. If you have comments, please mail them to the Line at ddil@episun1.harvard.edu. We will compile readers' views periodically and append them to the article.
This paper provides a historical review of the association of torsades de pointes, a rare form of ventricular arrhythmia which can result in cardiac arrest and death, with the use of two nonsedating antihistamines, terfenadine (Seldane®, Marion Merrell Dow) and astemizole (Hismanal®, Janssen).
The first clinically useful antiallergy medications, H1-receptor antagonists, were introduced in the early 1940s (Kaliner, 1992). Subsequently, the evolution of pharmacological research and the extensive use of antihistamines lead to the synthesis of many molecules with increased antihistaminic activity and fewer adverse effects (Passalacqua et al, 1993). Their efficacy in relieving symptoms of the immediate allergic response, namely rhinitis, itching, conjunctivitis, and urticaria, has rendered this class of drugs among the most commonly prescribed drugs and most commonly purchased over-the-counter medications in the United States (U.S.) (Krause, 1992).
Although traditional first-generation antihistamines are effective in preventing the symptoms of allergic rhinitis, their clinical use has often been limited by their substantial adverse event profile. Notably, most of the classic antihistamines bind non-specifically to cholinergic, adrenergic, and serotoninergic receptors; this explains the many adverse effects exerted on the autonomic nervous system (Passalacqua et al, 1993). In particular, sedation or drowsiness, which occurs in 10 to 20% of antihistamine users, may be so severe as to limit the drug's therapeutic usefulness (Kaliner, 1992). For example, the use of these agents has been associated with accidents in patients operating motor vehicles or machines (Smith, 1994).
In the last decade, several new or second-generation nonsedating antihistamines have been developed. These agents are lipophobic and highly bound to plasma proteins; consequently, their passage across the blood-brain barrier is minimal. This inability to penetrate the central nervous system (CNS) is primarily responsible for the lack of sedative and anticholinergic adverse effects associated with these agents. The advantage of the second-generation agents over the traditional antihistamines is therefore a result of their more favorable adverse event profile; specifically, the absence of intolerable CNS and anticholinergic adverse effects increases patient acceptance of and compliance with antihistamine therapy (Kaliner, 1992).
Prior to their introduction to the U.S. market, terfenadine and astemizole had been used in several European countries for a number of years. Serious adverse events had not been reported. The introduction of terfenadine (Seldane®) and, subsequently, of astemizole (Hismanal®) to the U.S. led to their rapid acceptance by both physicians and patients (Smith, 1994).
Torsades de pointes is a form of polymorphic ventricular tachycardia that is preceded by a prolongation of the QT interval (Monahan et al, 1990). Although this condition is found in many clinical settings, it is mostly induced by drugs and drug interactions that prompt a long QT syndrome (Monahan et al, 1990; Smith, 1994). Clinical symptoms of torsades de pointes include dizziness, syncope, irregular heartbeat, and sudden death (Monahan et al, 1990).
Terfenadine was approved for clinical use in the U.S. in 1985. At that time, no premonitory cardiovascular events had been associated with its use (Botstein, 1993). Its widespread acceptance during the two years following its introduction, despite its increased cost relative to traditional antihistamines, reflect the value to patients of its nonsedating properties. By mid-1987, Seldane® accounted for 55% of sales of single-entity antihistamines and 46% of antihistamine prescriptions (Kaliner, 1992).
In contrast to terfenadine, at the time of its approval in the United States in 1988, it had been known for several years that overdose with astemizole was associated with cardiovascular adverse events; notably, in one report, a patient developed heart block and torsades de pointes following an overdose with 200 mg astemizole (Craft, 1986).
By 1989, several cases of cardiotoxicity from overdose of terfenadine were reported as well. Specifically, 4 adults developed prolonged QT intervals with doses ranging from 120 to 240 mg/day; ventricular arrhythmias occurred 15 hours after overdose with 3.36 g (Davies et al, 1989).
In December, 1990, a group of physicians published a case report describing the first association of symptomatic torsades de pointes occurring with the use of terfenadine in a patient who was taking the recommended prescribed dose of this drug (Monahan et al, 1990); prior to this report, cardiotoxicity from terfenadine had only been reported in overdose. Interestingly, measured serum concentrations of the parent drug were high, while concentrations of the principal metabolite were reduced; in patients taking the recommended dose of this drug, 60 mg twice daily, serum concentrations are normally below assay detection limits. Moreover, in addition to terfenadine, the patient was taking cefaclor, ketoconazole, and medroxyprogesterone. Terfenadine is highly metabolized by the liver's P-450 oxidative pathways; ketoconazole is a well-known inhibitor of the P-450 metabolic pathways. The onset of symptoms and the occurrence of torsades de pointes after several days of ketoconazole therapy led the physicians to believe that an interaction between terfenadine and ketoconazole, specifically a ketoconazole-induced P-450 inhibition of terfenadine metabolism, resulted in the elevated terfenadine levels in plasma and in the cardiotoxicity previously only observed in cases of terfenadine overdose.
This report was highly significant for several reasons: firstly, it enhanced the awareness, by prescribing physicians, of this potentially serious drug interaction; secondly, it called the FDA's attention to this issue as well; in addition, it prompted Marion Merrell Dow, the manufacturers of Seldane®, to initiate a study of the interaction between terfenadine and ketoconazole; finally, it suggested that, theoretically, this finding could extend to the interaction of terfenadine with other drugs that inhibit P-450 metabolism (eg. erythromycin).
As of June, 1990, Marion Merrell Dow had accumulated data from 25 case reports that suggested that torsades de pointes could occur in patients as a result of terfenadine overdosage, or with recommended doses as a result of concomitant administration of ketoconazole or macrolide antibiotics, liver dysfunction, or cardiovascular disease. The reports were either cases of QT interval prolongation alone or in association with serious ventricular arrhythmias, or sudden death in an arrhythmic setting (Smith, 1994; Special Drug Communication Teleconference, 1992). These data were presented at an FDA Allergy and Pulmonary Advisory Committee meeting in June, 1990 (Kemp, 1992).
In view of the serious nature of the drug interactions associated with terfenadine, and specifically, of the importance of several potentially fatal drug interactions occurring with a widely used medication, Marion Merrell Dow modified their labeling for terfenadine in August, 1990. New information was added concerning the potentially serious alteration of terfenadine metabolism in patients receiving ketoconazole, macrolide antibiotics, and in patients with significant hepatic dysfunction (FDA Medical Bulletin, 1991). This modified labeling did not require from the FDA a "black box" warning (Kemp, 1992). In addition, Marion Merrell Dow issued 300 000 "Dear Doctor" letters to physicians and pharmacists reporting this labeling modification (Zechnich et al, 1994). Subsequently, a study initiated by Marion Merrell Dow as a result of their ongoing Product Surveillance Project confirmed the findings of Monahan et al.; specifically, that ketoconazole inhibits the metabolism of terfenadine (Eller and Okerholm, 1991). An ensuing interaction study confirmed that erythromycin alters the metabolism of terfenadine, leading to terfenadine accumulation and, consequently, altered cardiac repolarization (Honig et al, 1992).
By May, 1992, 83 serious cardiovascular events, including 15 deaths, had been received by Marion Merrell Dow and reported to the FDA. The reports included cases of QT interval prolongation, torsades de pointes, ventricular tachycardia, fibrillation, or flutter, cardiac arrest, and sudden death (Kemp, 1992). Of the reported deaths, 6 had underlying liver disease (Special Drug Communication Conference, 1992). Most of the arrhythmias occurred as a result of terfenadine overdosage (Kemp, 1992). QT interval prolongation and ventricular arrhythmias were reported in a cirrhotic patient who was treated with 240 mg daily terfenadine (Venturini et al, 1991). Torsades de pointes occurred in one patient whose daily dosage had been increased steadily over six weeks to 360 mg daily; this was the first reported case of torsades de pointes caused by an enhanced therapeutic dose of terfenadine in isolation (MacConnell and Stanners, 1991). In one reported case, torsades de pointes occurred in a patient who was taking the recommended prescribed dose of terfenadine in addition to ketoconazole (Zimmermann et al, 1992).
Furthermore, similar adverse events had been reported with the use of astemizole. Since its approval in 1988, 44 similar serious cardiovascular events had been reported through mid-1992 (Kemp, 1992). The reports included 23 cases of torsades de pointes, 10 cases of ventricular tachycardia, 9 cardiac arrests, and 5 cardiovascular deaths. Most of the cases occurred in patients overdosed with astemizole (Kemp, 1992). Torsades de pointes occurred in two patients who reported taking the normally prescribed doses of 10 or 20 mg daily (Simons et al, 1988; Snook et al, 1988).
By 1992, terfenadine had become the tenth most prescribed medication in the United States. Furthermore, it was apparent that concurrent prescribing of terfenadine, ketoconazole, and macrolide antibiotics persisted (Zechnich et al, 1994). In consideration of these issues, and following a review of the data available regarding the safety of terfenadine, the FDA recommended that Marion Merrell Dow modify their labeling for terfenadine to include a "black box" warning and additional information regarding the risk of serious cardiovascular events in patients taking terfenadine (Kemp, 1992; Nightingale, 1992).
Consequently, on July 7, 1992, Marion Merrell Dow issued 1.6 million letters to physicians and pharmacists reporting the modifications, and specifically, that a box warning had been added to the labeling of terfenadine (Zechnich et al, 1994). The warning stated that terfenadine is contraindicated in patients taking ketoconazole or erythromycin and in patients with significant hepatic dysfunction. In addition, the warning cautioned that the recommended dose of 60 mg twice daily should not be exceeded. Rare cases of serious cardiovascular adverse events, including death, cardiac arrest, torsades de pointes, and other ventricular arrhythmias had occurred in all of the above-mentioned clinical settings (FDA Medical Bulletin, 1992; Nightingale, 1992). In addition to these measures, a press statement was issued by the FDA to announce the contraindication to concomitant use of terfenadine with ketoconazole or erythromycin; these warnings were repeated in September, 1992 (Zechnich et al, 1994).
Similarly, at the recommendation of the FDA, Janssen, the manufacturer of astemizole, notified physicians, on July 20, 1992, that serious adverse cardiovascular events had been reported with large doses of astemizole and that the labeling of astemizole would be modified to warn against overdosing. In the months that followed this announcement, the FDA received two reports of torsades de pointes in patients who took astemizole 10 mg daily with erythromycin, or erythromycin together with ketoconazole. Subsequently, Janssen submitted to the FDA preliminary results of a pharmacokinetic study, initiated shortly after the terfenadine drug interactions were reported, indicating that concomitant use of astemizole and ketoconazole significantly increased plasma concentrations of astemizole. Consequently, the FDA requested that Janssen modify their labeling for astemizole to include a "black box" warning regarding this drug interaction. Therefore, on October 26, 1992, Janssen sent 600 000 "Dear Doctor" letters to physicians and pharmacists informing them of the new boxed warning for astemizole. The warning stated that concomitant administration of astemizole with ketoconazole, itraconazole, or erythromycin is contraindicated. This warning was repeated by the FDA in an October 28, 1992 press release (F-D-C Reports, 1992).
Marion Merrell Dow and Janssen have since closely monitored the safety of terfenadine and astemizole, respectively. Drug interactions and the influence of underlying disease states have been examined in pharmacokinetic and pharmacodynamic studies (Honig et al, 1993; Honig et al, 1993). In addition, the possible mechanisms that may generate torsades de pointes have been explored in pharmacoepidemiologic studies (Kemp, 1992). Currently, it appears that terfenadine and astemizole, when used as directed and in accordance with labeling instructions, are safe medications (Smith, 1994).
Terfenadine and astemizole may induce QT interval prolongation and ventricular arrhythmias, including torsades de pointes, in some patients in the following clinical settings: (1) overdosage; (2) concomitant administration of ketoconazole; (3) concomitant administration of erythromycin or macrolide antibiotics; (4) significant hepatic dysfunction; (5) preexisting cardiovascular disease (Smith, 1994). The existence of these risk factors and the widespread use of these drugs are elements that may explain the higher incidence of torsades de pointes than would have been expected otherwise.
The FDA and the manufacturers of terfenadine and astemizole have attempted to address these issues by identifying the subpopulations of patients at risk of torsades de pointes and announcing warnings in product labels, "Dear Doctor" letters, and various professional journals (Botstein, 1993). Currently, these drugs are available in the U.S. by prescription only. The FDA considers terfenadine and astemizole to be safe and effective drugs when used properly.
References
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Last updated: 8/23/95